Mountains of our future Earth: Defining priorities for mountain research

The Perth conferences, held every 5 years in Perth, Scotland, bring together people who identify as mountain researchers and who are interested in issues related to global change in mountain social-ecological systems. These conferences provide an opportunity to evaluate the evolution of research directions within the mountain research community, as well as to identify research priorities. The Future Earth Strategic Research Agenda provides a useful framework for evaluating the mountain research community\u27s progress toward addressing global change and sustainability challenges. Using a process originally set up to analyze contributions to the 2010 conference, the abstracts accepted for the 2015 conference in the context of the Future Earth framework were analyzed. This revealed a continued geographic underrepresentation in mountain research of Africa, Latin America, and South and Southeast Asia but a more even treatment of biophysical and social science themes than in 2010. It also showed that the Perth conference research community strongly focused on understanding system processes (the Dynamic Planet theme of the Future Earth research agenda). Despite the continued bias of conference contributions toward traditional observation- and conservation-oriented research, survey results indicate that conference participants clearly believe that transdisciplinary, transformative research is relevant to mountains. Of the 8 Future Earth focal challenges, those related to safeguarding natural assets, promoting sustainable land use, increasing resilience and understanding the water-energy-food nexus received considerable attention. The challenges related to sustainable consumption, decarbonizing socioeconomic systems, cities, and health were considerably less well represented, despite their relevance to mountain socioeconomic systems. Based on these findings, we outline a proposal for the future directions of mountain research

Mountains of Our Future Earth: Defining Priorities for Mountain Research: A Synthesis From the 2015 Perth III Conference

The Perth conferences, held every 5 years in Perth, Scotland, bring together people who identify as mountain researchers and who are interested in issues related to global change in mountain social-ecological systems. These conferences provide an opportunity to evaluate the evolution of research directions within the mountain research community, as well as to identify research priorities. The Future Earth Strategic Research Agenda provides a useful framework for evaluating the mountain research community's progress toward addressing global change and sustainability challenges. Using a process originally set up to analyze contributions to the 2010 conference, the abstracts accepted for the 2015 conference in the context of the Future Earth framework were analyzed. This revealed a continued geographic underrepresentation in mountain research of Africa, Latin America, and South and Southeast Asia but a more even treatment of biophysical and social science themes than in 2010. It also showed that the Perth conference research community strongly focused on understanding system processes (the Dynamic Planet theme of the Future Earth research agenda). Despite the continued bias of conference contributions toward traditional observation- and conservation-oriented research, survey results indicate that conference participants clearly believe that transdisciplinary, transformative research is relevant to mountains. Of the 8 Future Earth focal challenges, those related to safeguarding natural assets, promoting sustainable land use, increasing resilience and understanding the water-energy-food nexus received considerable attention. The challenges related to sustainable consumption, decarbonizing socioeconomic systems, cities, and health were considerably less well represented, despite their relevance to mountain socioeconomic systems. Based on these findings, we outline a proposal for the future directions of mountain research

Blockade of metallothioneins 1 and 2 increases skeletal muscle mass and strength

Abstract Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. Here, we demonstrate that these genes are also induced coincident with aging. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo, and found that concomitant abrogation of metallothionein 1 and 2 activates the Akt pathway, promotes myotube growth, specifically drives type IIb fiber hypertrophy and ultimately increases muscle strength. Silencing of metallothioneins results in elevated cytosolic zinc; increasing intracellular zinc levels are sufficient to mimic the effects of metallothionein blockade on myotube hypertrophy. We thereby provide direct evidence of the mechanisms by which metallothioneins can modulate skeletal muscle mass. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function are preserved in the presence of a strong catabolic stimulus: treatment with glucocorticoids. Taken together, our results suggest that blockade of metallothioneins constitutes a promising approach for the treatment of muscle diseases

Characterization of activating mutations of NOTCH3 in T cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies

Notch receptors have been implicated as oncogenic drivers in several cancers, the most notable example being NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). To characterize the role of activated NOTCH3 in cancer, we generated an antibody that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellular domain (ICD3), and sequenced the negative regulatory region (NRR) and PEST domain coding regions of NOTCH3 in a panel of cell lines. We also characterize NOTCH3 tumor-associated mutations that result in activation of signaling and report new inhibitory antibodies. We determined the structural basis for receptor inhibition by obtaining the first co-crystal structure of a NOTCH3 antibody with the NRR protein and defined two distinct epitopes for NRR antibodies. The antibodies exhibit potent anti-leukemic activity in cell lines and tumor xenografts harboring NOTCH3 activating mutations. Screening of primary T-ALL samples reveals that two of 40 tumors examined show active NOTCH3 signaling. We also identified evidence of NOTCH3 activation in 12 of 24 patient-derived orthotopic xenograft models, two of which exhibit activation of NOTCH3 without activation of NOTCH1. Our studies provide additional insights into NOTCH3 activation and offer a path forward for identification of cancers that are likely to respond to therapy with NOTCH3 selective inhibitory antibodies

Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength

Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo. We found that concomitant abrogation of metallothioneins 1 and 2 results in activation of the Akt pathway and increases in myotube size, in type IIb fiber hypertrophy, and ultimately in muscle strength. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function was also observed in the setting of glucocorticoid addition, which is a strong atrophy-inducing stimulus. Given the blockade of atrophy and the preservation of strength in atrophy-inducing settings, these results suggest that blockade of metallothioneins 1 and 2 constitutes a promising approach for the treatment of conditions which result in muscle atrophy

Discovery of a ZIP7 inhibitor from a Notch pathway screen

The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Generation and sequencing of a compound-resistant cell line identified a V430E mutation in ZIP7 that confers transferable resistance to the compound NVS-ZP7-4. NVS-ZP7-4 altered zinc in the ER, and an analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and investigate ZIP7 as a novel druggable node in the Notch pathway